Cervicovaginal secretory antibodies to human immunodeficiency virus type 1 (HIV-1) that block viral transcytosis through tight epithelial barriers in highly exposed HIV-1-seronegative African women.

Antibodies to human immunodeficiency virus (HIV) of the IgA, IgG, and IgM isotypes and high levels of the HIV suppressive beta-chemokine RANTES (regulated on activation, normally T cell expressed and secreted) were found in the cervicovaginal secretions (CVSs) of 7.5% of 342 multiply and repeatedly exposed African HIV-seronegative female sex workers. The antibodies are part of a local compartmentalized secretory immune response to HIV, since they are present in vaginal fluids that are free of contaminating semen. Cervicovaginal antibodies showed a reproducible pattern of reactivity restricted to gp160 and p24. Locally produced anti-env antibodies exhibit reactivity toward the neutralizing ELDKWA epitope of gp41. Study results show that antibodies purified from CVSs block the transcytosis of cell-associated HIV through a tight epithelial monolayer in vitro. These findings suggest that genital resistance to HIV may involve HIV-specific cervicovaginal antibody responses in a minority of highly exposed HIV-seronegative women in association with other protecting factors, such as local production of HIV-suppressive chemokines.

Detection of Y chromosome DNA as evidence of semen in cervicovaginal secretions of sexually active women.

The detection of traces of semen in cervicovaginal secretions (CVS) from sexually active women practicing unprotected sex is a prerequisite for the accurate study of cervicovaginal immunity. Two semen markers, the prostatic-specific antigen (PSA) and the Y chromosome, were detected in parallel in CVS obtained by a standardized vaginal washing of consecutive women attending the principal medical center for sexually transmitted diseases of Bangui, Central African Republic. PSA was detected by immunoenzymatic capture assay in the cell-free fraction of CVS, and the Y chromosome was detected by a single PCR assay of DNA extracted by silica from the cell fraction (Y PCR). Fifty (19%) cell-free fractions of the 264 beta-globin-positive CVS samples were positive for PSA, and 100 (38%) cell fractions of the CVS samples were positive for the Y chromosome. All the 50 (19%) PSA-containing CVS samples were also positive for the Y chromosome. Fifty (19%) CVS samples were positive only for the Y chromosome, with no detectable PSA. The remaining 164 (62%) CVS samples were both PSA and Y chromosome negative. These findings demonstrate that CVS from sexually active women may contain cell-associated semen residues unrecognized by conventional immunoenzymatic assays used to detect semen components. The detection of cell-associated male DNA with a highly sensitive and specific procedure such as Y PCR constitutes a method of choice to detect semen traces in female genital secretions.

Neutralizing antibodies and complement-mediated, antibody-dependent enhancement (C'-ADE) of human immunodeficiency virus infection in its vertical transmission.

PROBLEM: Mother-to-child transmission is a major route for the spread of human immunodeficiency virus (HIV) worldwide. Our understanding of its mechanisms and parameters is still limited. Among the factors possibly involved in virus passage determination are the level and quality of antiviral humoral response. METHOD OF STUDY: Anti-HIV-1/Lai neutralizing activity in sera from 35 mother-infant pairs (in which 13 transmission cases occurred) was investigated, as was the complement-mediated antibody-dependent enhancement capacity of the same sera. RESULTS: Neutralization titers of 640 or more were found only in four mothers of uninfected children, but this result was not significant. No significant link was obtained with the occurrence of complement-mediated, antibody-dependent enhancement. CONCLUSIONS: As suggested by a synthesis of the literature, vertical transmission of HIV is probably the result of multiple active and/or stochastic parameters in the mother, the fetal structures, and the viral population. The precise definition of cellular mechanisms involved in in utero infection would help to better define which immune activity in the mother should be more carefully considered.

Immune suppression and Th1/Th2 balance in pregnancy revisited: a (very) personal tribute to Tom Wegmann.

PROBLEM: The paradigm of local suppression necessary to understand the survival of the fetal allograft is often compared with the host-tumor relationship. METHODS: We investigated two components of local immune suppression: placenta-induced immunosuppression, which is mediated at least in part by a soluble factor of low molecular weight that can induce anergy in lymphocytes, and interleukin-10 (IL-10). RESULTS: We show that enhancement of IL-10 production in the decidua and placenta after alloimmunization requires the presence of Asialo GM1+ cells. Placenta-induced immunosuppression is linked with defects in phosphorylation of some components of the T cell receptor. CONCLUSION: NK cells could be in fact regulatory cells pushing maternal immune response toward a Th2 profile, beneficial for fetal survival, or toward a Th1 type of immune response, which acts in synergy. Modulation of TcR may represent a new mechanism for maternal-fetal tolerance.

Modulations of cytokine expression in pregnant women.

PROBLEM: Although the overall anti-infectious and anti-parasitic immunity of parous women appears normal, several aspects of maternal cell-mediated and humoral immunity are altered during pregnancy. This has been suggested to occur via preferential local and systemic secretion of Th-2 type cytokines, which down-regulate or prevent secretion/action of Th-1 type cytokines, in animals as well as in humans. METHOD: To evaluate the influence of gestation on the maternal immune system, we have measured, in pregnant women, the mRNAs coding for several cytokines (TNF alpha, IFN gamma, GM-CSF, IL-1 beta, IL-2, IL-4, IL-6, and IL-10) in peripheral blood mononuclear cells, by use of semi-quantitative RT-PCR. RESULTS: Our results show significant modulations of IFN gamma, IL-1 beta, IL-4, and IL-6 genes expression especially during the third trimester and near parturition. CONCLUSION: Cytokine expression is thus finely tuned in peripheral blood during pregnancy, in a previously unexpected complex pattern, related to gestational stage.

Clearance of HIV infection in 12 perinatally infected children: clinical, virological and immunological data.

OBJECTIVE: A case of HIV infection clearance in a perinatally infected infant has been recently reported. We report here on the molecular, biological and clinical features of such virus clearance in 12 children. DESIGN AND METHODS: We performed a retrospective analysis of the diagnosis in our 6-year cohort of 188 children born to HIV-seropositive mothers. HIV-1 was detected by coculture of infant peripheral blood mononuclear cells (PBMC) with cord blood cells, direct culture of infant cells, and DNA polymerase chain reaction (PCR). The children were diagnosed three times during the first 3 months of life and then followed up over a postnatal period of 18-36 months. RESULTS: The 12 reverted children had at least two positive PCR in at least two amplified regions. Among them, six were tested positive in culture/coculture assay, and five were treated long-term with zidovudine. Thus, seven out of 12 reversions cannot be attributed to antiretroviral therapy. All the virological results became negative during the first year of life, and serology lowered to negative values between 9 and 23 months. We could not find any correlation between either neutralizing or antibody-dependent cellular cytotoxicity-mediating antibodies and HIV clearance. CONCLUSION: In our cohort, we showed that an unexpected number of children born to HIV-seropositive mothers (6.7%) cleared HIV infection during the first year of life, and subsequently became seronegative. Interestingly, most of these children exhibited unspecified clinical signs during the first months of life. Five of these children were tested positive only by PCR, which suggests a low virus load and could, at least partly, explain spontaneous clearance. However, 4 years later, among the seven remaining infants, two seronegative children presented recurrent hepatosplenomegaly, which may indicate the presence of hidden virus not detectable by peripheral blood testing.

A propos des marqueurs du VIH : marqueurs biologiques de suivi au cours de l'infection par le virus de l'immunodeficience humaine

"L'infection par le VIH evolue classiquement en trois phases : seroconversion; phase de latence clinique; apparition des signes cliniques de ""presida"" puis SIDA. entre l'etape du diagnostic serologique et la periode de la maladie ou sont utilisables les differentes classifications cliniques; peut donc exister une longue periode de latence clinique. Mais l'infection par le VIH est une maladie chronique et l'erosion du systeme immunitaire commence des la seroconversion et va se traduire par des anomalies biologiques. Ces anomalies seront autant de marqueurs utilisables pour determiner precocement le degre d'evolutivite de l'infection par le virus de l'immunodeficience humaine (VIH). De tels marqueurs sont indispensables pour la prise en charge des malades. Parmi ceux-ci quatre marqueurs biologiques independants; predictifs d'evolutions pejoratives a court terme (36 mois) peuvent etre utilises : deux marqueurs specifiques du VIH; l'antigenemie p24 et le titre en anticorps anti p24; deux marqueurs indirects non specifiques du VIH: la B2 microglobulinemie et le nombre absolu des lymphocytes CD4 circulants. En dehors de ces marqueurs biologiques classiques; de nombreux autres marqueurs ont ete evalues sans que leur interet pratique n'ait ete bien defini. Dans le futur les criteres biologiques previsionnels actuels seront certainement completes voire remplaces par l'evaluation virologique quantifiee de la charge virale"

Marqueurs biologiques d'immunopression chez les malades tuberculeux seropositifs

La double infection du VIH et de la tuberculose en Afrique de l'Ouest connait aujourd'hui une augmentation considerable. Ainsi une etude a ete menee en vue d'evaluer le degre d'atteinte immunitaire des patients seropositifs lors du diagnostic de la tuberculose ; d'ameliorer la definition du SIDA chez les patients et de proposer les marqueurs alternatifs aux marqueurs classiques d'immunodepression. Lors du diagnostic de la tuberculose seuls 33 pour cent des patients presentaient biologiquement du SIDA